1986 Nobel Prize in Physiology or Medicine — Cohen and Levi-Montalcini, Discovery of Growth Factors

What You'll Learn in This Article

You will understand the answer to the question: How do cells know when to grow, where to extend, and when to stop? It explores the story of how Rita Levi-Montalcini's nerve growth factor (NGF) research, which began in a home laboratory in Fascist Italy, led to the discovery of nerve growth factor (NGF), and how her collaboration with Stanley Cohen expanded to the discovery of epidermal growth factor (EGF). You will also learn how this discovery has led to today's Alzheimer's and Parkinson's disease treatments, EGFR-targeted anticancer drugs (gefitinib and erlotinib), burn treatments, and even EGF cosmetics.

A Story Different from Common Knowledge — Cells Don't Grow on Their Own

When we say that a body grows, we imagine that cells expand and extend on their own. Muscle growth, wound healing, and nerve regeneration seem like individual decisions made by each cell.

Levi-Montalcini and Cohen revealed the opposite of this common knowledge. Cells do not grow on their own. They must receive a signal to grow, a signal to extend in a certain direction, and a signal to stop. The substance that carries these signals is called a growth factor. It is a powerful signaling molecule that directs cells in tiny amounts.

Nerve growth factor (NGF) promotes the growth of nerve cells. When this substance binds to specific receptors on the cell membrane, it activates proteins within the nerve cell that promote the growth of axons. When axons extend and meet other nerve cells, synapses are formed, completing a neural circuit.

Epidermal growth factor (EGF) is responsible for the growth and maintenance of epithelial cells, such as those found in the skin and digestive tract. It is a small molecule protein similar in amino acid sequence to NGF. It is essential for wound healing, regeneration, and tissue maintenance.

In the language of computer science, growth factors are event-triggered signals. Cells are always in a waiting state, and when a specific signal arrives, they change their state. The receptor is an event listener, and the signal transduction cascade is a callback chain. When NGF binds to the TrkA receptor → the receptor phosphorylates itself → downstream signaling proteins are sequentially activated → and finally, the axon growth gene is expressed. This is remarkably similar to the pipeline of event brokers → listeners → handlers → actions that we are now familiar with in microservices architecture.

The implications of this perspective are profound. By manipulating growth factors and their receptors, we can manipulate the fate of cells. This is the foundation of today's tissue regeneration medicine, targeted anticancer drugs, and treatments for neurodegenerative diseases.

The Context of the Time — Challenger and Chernobyl, Two Major Disasters

1986 was the year when humanity witnessed the vulnerability of advanced technology on two major occasions.

On January 28, in world history, the Space Shuttle Challenger exploded in the sky 73 seconds after launch. All seven crew members were killed. Among them, Christa McAuliffe was the first civilian in space and an elementary school teacher. The impact was even greater because students across the United States were watching the launch live. The cause was a defect in the O-rings (rubber seals) that stiffened in the cold. On April 26, the Chernobyl nuclear power plant's No. 4 reactor exploded in the Soviet Union's Ukraine, the worst nuclear accident in human history. Radioactive fallout spread across Europe, and a 30km radius was designated as an exclusion zone. These two events shook the confidence in the advanced technology systems of the two superpowers.

In February, the People Power Revolution took place in the Philippines, overthrowing Marcos' 20-year dictatorship and making Corazon Aquino president. This was a symbolic victory for Asian democratization. On March 13, Microsoft was listed on NASDAQ — Bill Gates became the youngest billionaire at age 31, and a financial foundation was laid for the company to solidify its position as a standard in personal computing 20 years later.

In Korean history, the Seoul Asian Games were held from September 20 to October 5 — a rehearsal for the 1988 Olympics. Korea achieved second place in the overall standings. This was a moment when the country's urban infrastructure and international event management capabilities were revealed to the world. In June, the Bucheon sexual assault case was revealed, in which police officer Moon Gwi-dong sexually assaulted a labor activist, Kwon In-suk. This was followed by attempts by the prosecution to cover up the case and legal battles, which became one of the triggers for the June Democratic Struggle of 1987.

In this year of disaster and upheaval, the Nobel Committee recognized the two individuals who revealed the microscopic signaling system of cell growth. In a year when the fragility of large systems was revealed, the discovery that a tiny signaling molecule controls the life system was recognized.

Rita Levi-Montalcini — A Journey That Began in a Home Laboratory During the Mussolini Era

Rita Levi-Montalcini (1909-2012) was an Italian neurobiologist. Her life story is one of the most dramatic narratives of a 20th-century female scientist.

Born in Turin, Italy, into a Jewish family, she faced obstacles from the beginning. Her patriarchal and conservative father believed that women should only play the roles of wife and mother and sent her to a girls' school. Rita, who wanted to study science, taught herself Latin, Greek, and mathematics in 8 months to complete the regular high school curriculum, and finally persuaded her father to enroll in the medical school at the University of Turin — she received her Ph.D. in medicine in 1936.

However, the Fascist Mussolini regime enacted anti-Jewish laws, which blocked her academic career. Although she graduated with excellent grades, there was nowhere for her to conduct research, and she could not even use the university library. She was excluded from academia because she was Jewish.

Her response was remarkable. With the help of her family, she set up a laboratory in her home. She had a microscope, a culture dish she made herself, and experimental equipment she made herself. Her materials were chicken eggs purchased from the market. She began studying how the nervous system of developing chicken embryos forms.

The key was a decisive experiment. She read Viktor Hamburger's paper on the formation of the embryonic nervous system and was inspired to try an experiment in which she removed the limb bud from a chicken embryo. As a result, the nervous tissue that should have grown into that area atrophied. Conversely, when the limb bud was transplanted, the nerve cells regrew. This was strong evidence that the tissues of the embryo send signals to the nerve cells to grow.

After the war, she was invited to the United States and served as a professor at Washington University (St. Louis) from 1956 to 1977, continuing this research. Here, she succeeded in isolating a highly active growth-promoting substance from snake venom and mouse salivary glands — this substance was later named nerve growth factor (NGF). From 1969 to 1978, she also served as the director of the Cell Biology Research Institute of the Italian National Academy of Sciences.

Levi-Montalcini's later years were exceptionally long and active. She continued her research and social activities well past the age of 100 and was appointed as a lifetime senator in the Italian Senate in 2001, where she continued to contribute to science and technology policy until the end of her life. She died in 2012 at the age of 103 — the oldest Nobel laureate in Physiology or Medicine.

Stanley Cohen — Continuous Collaboration and the Discovery of EGF

Stanley Cohen (1922-2020) was an American biochemist. He received his Ph.D. from the University of Michigan in 1948 and worked as a researcher in Victor Hamburger's laboratory at Washington University from 1952 to 1958 — where he met Levi-Montalcini and their collaboration began. Later, he served as a professor at Vanderbilt University from 1967.

Cohen's key contribution was the determination of the chemical identity of NGF and the discovery of EGF.

In the NGF research, Cohen determined the chemical properties of the active substance that Levi-Montalcini had isolated from snake venom and mouse salivary glands. He showed that this substance was a protein and that it acts by binding to specific receptors on the cell membrane.

Cohen then isolated another substance from mouse salivary glands — a substance that causes the eyelids of young mice to open prematurely and their teeth to erupt prematurely. He named this substance epidermal growth factor (EGF). Human EGF was later isolated and purified, and its amino acid sequence was determined, as well as the epidermal growth factor receptor (EGFR) on the cell membrane.

EGFR is a receptor tyrosine kinase (RTK) — when EGF binds, the receptor itself acts as an enzyme that phosphorylates tyrosine. This phosphorylation triggers a downstream signal transduction cascade. This concept became the standard model for growth factor receptor signal transduction research.

CS Framework — Event Listeners and Callback Chains

If we reconstruct the growth factor signaling system in the language of computer science, it would be as follows:

Growth Factor = Event-Triggered Payload: Growth factors such as NGF and EGF are payloads that contain an event to "grow" a specific cell. They are very small molecules (hundreds of amino acids) but are powerful state transition triggers.

Receptor = Event Listener: The receptors on the cell membrane are listeners that recognize only specific growth factors. The TrkA receptor recognizes only NGF, and the EGFR recognizes only EGF. The specificity of the listener is determined by the precise match of its three-dimensional structure.

Receptor Autophosphorylation = Listener Activation: When a growth factor binds, the receptor forms a dimer and phosphorylates itself — this is similar to the listener changing its state to an "active" flag.

Signal Transduction Cascade = Callback Chain: The phosphorylated receptor activates adapter proteins (Grb2, Shc), which sequentially trigger a cascade of Ras/Raf/MEK/ERK, etc. Each step is a callback from the previous step. It has a structure similar to the promise chain in functional programming.

Final Action = Change in Gene Expression: The end point of the cascade moves to the nucleus, activates specific transcription factors, and changes the expression of specific genes — a fundamental reconfiguration of cell state.

Gating = Apoptosis When Growth Factor is Lacking: Interestingly, cells undergo apoptosis (programmed cell death) when there is no growth factor signal. This is similar to the pattern in CS where a process terminates itself if it does not receive a heartbeat signal. The system design philosophy is "if there is no one sending you signals, you are not needed."

Hacking = Targeted Anticancer Drugs: Cancer cells often have mutations that constantly activate growth factor receptors. In particular, activating mutations in EGFR are found in a significant proportion of non-small cell lung cancers. EGFR tyrosine kinase inhibitors, such as gefitinib (Iressa) and erlotinib (Tarceva), specifically block this constantly activated receptor, inhibiting the growth of cancer.

Limitations of this analogy: Cell signaling operates as a probabilistic gradient rather than a spike, and multiple signals are integrated in parallel. It is much more complex than a simple event → callback model.

Scholarly Impact: The Era of Growth Factors and Targeted Therapy

Following this discovery, research on growth factor families expanded dramatically.

Expansion of Growth Factor Families: Subsequent discoveries included numerous growth factor families—such as VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), PDGF (platelet-derived growth factor), IGF (insulin-like growth factor), TGF (transforming growth factor), and BDNF (brain-derived neurotrophic factor). Each has its own signaling system and specific receptor.

The Era of Targeted Cancer Drugs: Various drugs targeting growth factor receptors were developed.

• EGFR Inhibitors: Gefitinib (2003), Erlotinib (2004), Osimertinib (2015) – for lung cancer
• HER2 Targeting: Trastuzumab (1998), Lapatinib (2007), Pertuzumab (2012) – for breast cancer
• VEGF Inhibitors: Bevacizumab (2004), Aflibercept (2011) – for colorectal cancer and macular degeneration
• BCR-ABL: Imatinib (2001) – for chronic myelogenous leukemia (Gleevec, the beginning of the era of targeted cancer drugs)

Attempts to Treat Neurodegenerative Diseases: Clinical trials using NGF and its related substances to treat Alzheimer's and Parkinson's diseases are underway. Experiments involving the transplantation of genetically engineered NGF-producing cells into the brains of Alzheimer's patients have shown delayed destruction of brain cells.

Tissue Regeneration Medicine: EGF has been clinically applied to promote skin regeneration in burn patients and to treat corneal ulcers and bedsores. In Korea, Daewoong Pharmaceutical's recombinant human EGF was commercialized in 2001 (Easyeff), marking the world's first such case. Starting as a burn treatment, it has expanded to scar recovery and cosmetic ingredients.

Korea's Legacy and Today

In Korea, the impact of this legacy is also evident. Since the late 1990s, laboratories at Seoul National University, Yonsei University, POSTECH, and KAIST have been actively conducting research on growth factors and signal transduction.

Daewoong Pharmaceutical's commercialization of EGF (2001, the first in the world) is a significant industrial achievement. Starting with Easyef, a burn and wound healing agent, it has since expanded into cosmetic ingredients. Today, Korean EGF cosmetics are one of the pillars of the K-beauty industry. The combination of AHA/BHA, EGF, and peptides is a representative formula in Korean skincare.

In clinical practice, EGFR-targeted cancer drugs are routinely prescribed at Seoul Asan Hospital, Samsung Seoul Hospital, Seoul National University Hospital, and Severance Hospital. Because 30-40% of Korean patients with non-small cell lung cancer have EGFR-activating mutations, the prescription of osimertinib and gefitinib is very active. The fact that the EGFR mutation profile in Koreans is different from that of Westerners is a key basis for personalized cancer treatment.

Why is it Important?

What the two scientists left behind is the establishment that "cells determine their fate based on signals from their neighbors."

The implications of this proposition are far-reaching. In developmental biology, it opened up the picture of how embryonic morphogenesis is organized by growth factor gradients; in regenerative medicine, it opened up the possibility of artificially inducing tissue regeneration; in oncology, it revealed that the uncontrolled proliferation of cancer cells is due to dysfunction of growth factor signaling; and in neuroscience, it elucidated the principles of brain circuit formation and maintenance.

Levi-Montalcini's life story is itself a symbol of this award. She started her research in her family's laboratory, overcoming the discrimination against Jews under the Fascist regime, and 30 years later, she received the Nobel Prize, and continued her active research until she was over 100 years old. It is a symbol that no matter how oppressive the environment, intellectual curiosity will not be hindered. Mussolini's Italy could not stop her research, nor could the passage of time.

The symbol of collaboration is also strong. Levi-Montalcini and Cohen worked side-by-side for eight years at the University of Washington, complementing each other's weaknesses. And this collaboration led to the academic peak of both scientists.

Following this award, the flow of research on growth factors, signal transduction, and tissue regeneration has continued:

• 1988, Black, Elion, and Hitchings – mechanism of drug action (receptor targeting)
• 1989, Bishop and Varmus – oncogenes and tumor development
• 1994, Gilman and Rodbell – G protein-coupled receptor signal transduction
• 2000, Carlsson, Greengard, and Kandel – neurotransmission in the nervous system

Clinical and industrial applications of this discovery:

• Targeted cancer drugs: Imatinib (2001), Trastuzumab (1998), Osimertinib (2015), etc.
• VEGF inhibitors: Ranibizumab, Aflibercept (macular degeneration)
• NGF/BDNF family: clinical trials for Alzheimer's and Parkinson's diseases
• Commercialization of recombinant EGF: burn treatment, cosmetic ingredients
• CAR-T cell therapy: fusion of antibody specificity and growth factor receptor concept

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